Photodynamic therapy (“PDT”) is a process whereby light of a specific wavelength is directed to tissues undergoing treatment or investigation that have been rendered photosensitive through the administration of a photoreactive or photosensitizing agent. The objective of the intervention may be either diagnostic, where the wavelength of light is selected to cause the photoreactive agent to fluoresce, thus yielding information about the tissue without damaging the tissue, or therapeutic, where the wavelength of light delivered to the photosensitive tissue under treatment causes the photo-reactive agent to undergo a photochemical interaction with oxygen in the tissue under treatment that yields high energy species, such as singlet oxygen, causing local tissue lysing or destruction. The method of van Lier (Photobiological Techniques 216: 85-98 (Valenzo et al. eds. 1991)) can be used to confirm the ability of any given compound to generate singlet oxygen effectively, thus making it a good candidate for use in photodynamic therapy.
In photodynamic therapy, a photosensitizer compound that demonstrates the ability to selectively accumulate in target tissue, such as neoplastic or hyperproliferative tissue, is administered to a subject, and when the photosensitizer accumulates in or preferentially associates with the target tissue, the target tissue becomes sensitized to photoradiation. The photo-sensitizing agent can be activated either coherent (laser) or non-coherent (non-laser) light. It is currently accepted that following absorption of light, the photosensitizer is transformed from its ground singlet state (P) into an electronically excited triplet state (3P*; T˜10−2 sec.) via a short-lived excited singlet state (1P*; T˜10−6 sec.) The excited triplet can undergo non-radiative decay or participate in an electron transfer process with biological substrates to form radicals and radical ions, which can produce singlet oxygen and superoxide (O2−) after interaction with molecular oxygen (O2). Singlet oxygen can be produced from molecular oxygen by the transfer of energy directly or indirectly from the activated photosensitizer Singlet oxygen is one of the agents responsible for cellular and tissue damage in PDT, causing oxidation of the target tissue; there also is evidence that the superoxide ion may be involved. The generation of these cytotoxic agents plays a role in tumor homeostasis and the observed tumor destruction.
Photodynamic therapy has proven to be very effective in destroying abnormal tissue such as cancer cells. In this therapy, a photoreactive agent having a characteristic light absorption wavelength or waveband is first administered to the patient, typically either orally or by injection. Abnormal tissue in the body is known to selectively absorb certain photoreactive agents to a much greater extent than normal tissue, e.g., tumors of the pancreas and colon may absorb two to three times the volume of these agents, compared to normal tissue. Certain porphyrins and related tetrapyrrolic compounds tend to localize in abnormal tissue, including malignant tumors and other hyperproliferative tissue, such as hyperproliferative blood vessels, at much higher concentrations than in normal tissues, so they are useful as a tool for the treatment of various type of cancers and other hyperproliferative tissue by photodynamic therapy (PDT) (T. J. Dougherty, C. J. Gomer, B. W. Henderson, G. Jori, D. Kessel, M. Kprbelik, J. Moan, Q. Peng, J. Natl. Cancer Inst. 90: 889 (1998), incorporated here by reference). However, most of the porphyrin-based photosensitizers including PHOTOFRIN® (a purified hematoporphyrin derivative (HpD) approved worldwide for the treatment of tumors) clear slowly from normal tissue, so patients must avoid exposure to sunlight for a significant time after treatment.
PDT with PHOTOFRIN® has been used to treat a multiplicity of tumors accessible to light, including skin, lung, bladder, head and neck, breast, gastric, cervical and esophageal cancers. PHOTOFRIN® has some desirable characteristics, including good efficacy, water solubility, good yield of singlet oxygen, and ease of manufacture. However, PHOTOFRIN® has some disadvantageous properties: (i) it is a complex mixture of porphyrin dimers and higher oligomers linked by ether, ester, and/or carbon-carbon bonds and, therefore is difficult to study; (ii) it shows skin phototoxicity in patients for four to six weeks after administration; and (iii) due to its relatively weak absorbance in the red region (630 nm), lack of penetration of light through tissue limits current clinical applications of PHOTOFRIN® in PDT to the destruction of cancerous tissue less than 4 mm from the source of light used in the therapy.
Thus, there is a need for additional photosensitizers for use in PDT, diagnostic and therapeutic applications.